Lewis acid induced anomerization of Se-glycosides. Application to synthesis of α-Se-GalCer

Article abstract of DOI:10.1021/acs.orglett.5b03591

The TiCl₄ induced anomerization of selenium glycosides of galacturonic acid derivatives is reported. The reaction was successful for galacturonic acid when various alkyl, alkenyl, alkynyl, saccharide, steroid, and lipid groups were attached to

Full text of DOI:10.1021/acs.orglett.5b03591

Letter
pubs.acs.org/OrgLett
Lewis Acid Induced Anomerization of Se-Glycosides. Application to
Synthesis of α-Se-GalCer
Anthony W. McDonagh,† Mary F. Mahon,‡ and Paul V. Murphy*,†
†School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
‡Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom
S
* Supporting Information
ABSTRACT: The TiCl4 induced anomerization of selenium
glycosides of galacturonic acid derivatives is reported. The
reaction was successful for galacturonic acid when various
alkyl, alkenyl, alkynyl, saccharide, steroid, and lipid groups
were attached to the anomeric Se atom. An increased amount
of TiCl4 and/or higher temperature were needed to ensure
completion of the reaction in some cases. Yields were higher
for reactions carried out at higher dilution. The reaction was
applied to the synthesis of Se-based mimics of the potent
immunostimulant α-GalCer (KRN7000).
arbohydrates play important roles in many biological
selenium and tellurium has been less explored in carbohydrate
chemistry. Selenoglycosides have been investigated as glycosyl
donors in glycoside formation7 as well as having application in
X-ray crystallography.8 There have been various procedures for
the synthesis of β-Se-glycosides (or equatorial glycosides)9 and
a lesser number reported for α-Se-glycosides (or axial
glycosides), which included the in situ production of an axial
selenolate anion.10 Herein is disclosed the results of our recent
investigation into the Lewis acid promoted formation of axial
glycosyl selenides from the corresponding equatorial anomer.
The methodology has been applied to various Se-glycosides,
including the α-selenoglycoside analogue of the potent
immunostimulant KRN7000 (α-GalCer).
1
Cprocesses,
and the configuration of their glycosides
influence their properties. The Lewis acid promoted anome-
rization of equatorial glycosides generally give rise to axially
oriented glycosides, which can be favored due to the anomeric
effect.2 Lewis acids TiCl4 and SnCl4 have proven effective for
the anomerization of various O-, N3-, and S-glycosides derived
from uronic acids, giving good outcomes in terms of anomeric
selectivity and product yield. The presence of the carbonyl
group at C-6 of the uronic acid leads to a significant increase,
through chelation (Scheme 1), in the rate of anomerization
compared to the corresponding reduced pyranoside.3,4
The investigation commenced with the synthesis of propyl β-
Se-glycosides, which were based on both galactopyranose and
the corresponding galacturonic acid 2β, 3β, 9β, and 10β
(Scheme 2). Ishihara and co-workers have reported the
synthesis of peracetylated galactose and glucose β-selenides
from a β-glycosyl p-methylbenzoselenoate, which is a selenolate
precursor.11 Hence, the benzoselenoate 1 was treated with
piperazine, and this was followed by addition of 1-
bromopropane to give β-selenide 2β. Protecting group
exchange provided 3β. Attempts to form benzoselenoate 7
and 8 from α-glycosyl bromides 5 and 6 with Ishihara
conditions gave the desired products in low yields. However,
ultrasonication of 4 in the presence of 5 or 6 for 15 min in
DMF led to improved yields (63−70%). Subsequently reaction
of 7 and 8 with propyl bromide provided 9β and 10β.
Scheme 1. Lewis Acid Induced Anomerization of Glycosides
via Endocyclic Cleavage
The substitution of the oxygen atom in glycosidic bonds for
other elements such as carbon or sulfur has proven attractive as
a strategy to obtain glycomimetics for study of their properties.5
Glycomimetics could be more stable than native glycosides or
be useful in vaccine development. In recent years, the synthesis
of S-glycosidic analogues of oligosaccharide, glycolipids, and
glycomimetics has been studied.6 Substitution of oxygen for
Attention was next turned to the anomerization reaction.
Previous study with O- and S-glycosides have shown that use of
2.5 equiv of Lewis acid in CH2Cl2 to be effective, and these
Received: December 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03591
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Equatorial Selenoglycosides
Table 1. Investigation of Reagents and Conditions
Lewis
acid
concn
(μM)
outcome (isolated
yield)
entry β-Se-glycoside
t (°C)
1
2β or 3β
2β or 3β
3β
TiCl4
TiCl4
SnCl4
SnCl4
SnCl4
SnCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
−15
rt
100
100
100
90
90
90
90
90
7
no 2α/3α
no 2α/3α
no 3α
2
3
rt
4
9β
rt
no 9α
5
9β
0
no 9α
6
9β
−20
rt
no 9α
7
9β
no 9α
8
9β
4
9α (58%)
9α (94%)
10α (46%)
10α (68%)
10α (86%)
10α (94%)
9
9β
−20
0
10
11
12
13
10β
10β
10β
10β
80
70
15
7
−40
−20
−20
conditions were chosen as the starting point for the
investigation. Compounds 2β and 3β were treated with SnCl4
or TiCl4 at various temperatures, but no α-selenoglycoside
could be observed or isolated, with the reactions carried out at
room temperature providing the corresponding glycosyl
chloride; reactions at lower temperature led only to the
recovery of 2β and 3β. Galacturonates 9β and 10β were then
studied, and it was found that carrying out the reaction at −20
°C in the presence of TiCl4 led to successful formation of 9α
and 10α in moderate yield. Higher temperatures with TiCl4 led
to glycosyl chlorides in these cases. Reactions with SnCl4 did
not give the α-anomer with only the glycosyl chloride being
obtained. There is evidence that α-selenocarbenium ions are
generated from O,Se acetals/ketals in the presence of TiCl4 and
that this is not the case for SnCl4, where oxocarbenium ions
have instead been preferred, due to Sn(IV)’s affinity for Se.12
The results herein are thus consistent with TiCl4 promoting
endocyclic cleavage to give α-selenocarbenium ions and
anomerization whereas reaction with SnCl4 may proceed by
breaking the anomeric C to Se bond leading only to glycosyl
chloride formation. On lowering the concentration of all
reactants, it was observed that the yields increased for both 9α
and 10α, up to 94% (Table 1). The stereochemistry of the α-
Figure 1. Structures of 9α/10α.
of various equatorial Se-glycosides 11β−15β and 22β gave the
corresponding axial glycosides 11α−15α and 22α in good to
excellent yield and selectivity. Allyl glycoside 16β was found to
require extra TiCl4 at −20 °C, while anomerization of the
propargyl glycoside 17β required both increased TiCl4 and
higher temperature (0 °C). The same trend was observed for
glycolipid 18β, requiring the reaction to be carried out at room
temperature. The double anomerization reaction of bivalent
saccharide 19β proceeded smoothly at −20 °C to give 19α with
again a higher quantity of promoter being needed. Anomeriza-
tion of disaccharides 20β and 21β also required additional
TiCl4 and higher temperature to maximize the yield of the axial
anomer. A higher yield was obtained for the allyl ester 21β
compared to the methyl ester 20β in line with a faster rate
noted previously for an allyl ester of O-glycoside of a glucuronic
acid derivative when compared to the corresponding methyl
ester.4 The requirement for higher temperature and more Lewis
acid can be rationalized on the basis of increasing electron-
withdrawing properties of the aglycon and an increase in
number of sites that can coordinate to the Lewis acid.
1
selenide was confirmed by H NMR (J1,2 = 4−5 Hz) and by
determination of the single X-ray crystal structure of 10α
(Figure 1). The C−Se bond length (1.98 Å), the C−Se−C
angle (97°), and the C−Se−C distance (2.97 Å) were in
agreement with predicted values.13 These values can be
compared to typical C−O, C−S bond lengths (1.4, 1.8 Å),
C−O−C, C−S−C bond angles (115°, 95°), and C−O−C, C−
S−C distances (2.4, 2.9 Å).
A series of benzoylated β-selenides 11−22β were next
prepared to examine the wider scope of the anomerization
reaction (Scheme 3). Benzoylated derivatives were selected for
study, given they have been found to be generally superior to
corresponding acetylated saccharides, in particular for the
anomerization of disaccharides or glycolipids.3g,i Thus, reaction
To further demonstrate an application of the reaction, we
investigated its suitability for preparation of the Se-glycoside
mimic of the immunostimulant α-GalCer (KRN7000).14 One
important feature of α-GalCer is the axial orientation of the
substituent on the anomeric carbon. The parent O-glycolipid
has been shown to stimulate high production of T helper 1
B
DOI: 10.1021/acs.orglett.5b03591
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cells by the T cell receptor (TCR) on natural killer T (NKT)
cells. The production of IFN-γ cytokines can assist in
antitumor, antiviral, and antibacterial infections while IL-4
cytokines assists in alleviating the effects of autoimmune
diseases. However, despite this high cytokine production IFN-γ
and IL-4 antagonize each other’s biological functions. It has
therefore been an attractive approach to synthesize various
analogues of KRN7000 to try to identify compounds what
would promote a bias in cytokine production.15 Analogues
prepared previously include C-16 and S-glycosides,17 both of
which show interesting properties.
Scheme 3. Anomerization of Various Se-Galacturonides
The synthesis of α-Se-GalCer commenced from phyto-
sphingosine 23 (Scheme 4).18 Reaction of the primary alcohol
Scheme 4. Synthesis of Se-KRN7000 and Acid Analogue
of 23 with methane sulfonyl chloride provided 24, and this was
immediately coupled with 8 to give β-glycolipid 25 in moderate
yield. The introduction of other leaving groups (OTf, I, Br, Cl)
at the primary alcohol 23 led to a facile formation of an
oxazoline byproduct, the rate of formation of which was
reduced for the mesylate, enabling Se-alkylation to take place.
Anomerization of 25 with TiCl4, in the presence of a large
amount of the promoter, provided 26 in excellent yield. Next,
the selective cleavage of the methyl ester on 26 with LiI in
EtOAc provided 27.19 Removal of all benzoate esters from 27
with NaOMe−MeOH gave the galacturonic acid analogue of α-
GalCer 30.20 On the other hand, chemoselective activation of
the carboxylic acid of 27 with PyBOP followed by one-pot
reduction of the resulting hydroxybenzotriazoyl ester with
NaBH4 furnished primary alcohol 28.21 Removal of benzoyl
groups from 28 completed the synthesis of α-Se-GalCer 29.
In summary, we have disclosed a convenient chelation-
induced anomerization reaction for the generation of axial or α-
Se-glycosides from corresponding equatorial or β-anomers. The
methodology has been shown to have wide scope and can
accommodate a variety of functionality on the glycoside. The
increasing complexity of the aglycon led to the requirement to
increase the amount of Lewis acid. Nevertheless in the
(IFN-γ) and T helper 2 (IL-4) cytokines via recognition of the
bound glycolipid to the CD1d protein on antigen-presenting
C
DOI: 10.1021/acs.orglett.5b03591
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Letter
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glycosides of the potent immunostimmulant KRN7000 which is
now available to contribute to structure−activity relationships.
In addition, other α-Se-glycosides will be accessible by this
approach.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03591.
■
S
Crystallographic data for 10α, which can be obtained
from the Cambridge Crystallographic Data Centre,
CCDC 1446829 (CIF)
NMR Spectra (PDF)
Experimental Section (PDF)
AUTHOR INFORMATION
Corresponding Author
■
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*E-mail: paul.v.murphy@nuigalway.ie.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The research was supported by the Irish Research Council
(PhD Scholarship to A.McD.) and NUI Galway (College of
Science PhD scholarship to A.McD.). This publication has also
emanated in part from research supported by Science
Foundation Ireland (SFI, Grant Number 12/IA/1398) and is
cofunded under the European Regional Development Fund
under Grant Number 14/SP/2710.
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Org. Lett. XXXX, XXX, XXX−XXX